The invention relates to novel phthalazinone-derivatives which are used in the pharmaceutical industry for the production of medicaments.
International Patent Applications WO98/31674, WO99/31071, WO99/31090 and WO99/47505 disclose phthalazinone derivatives having selective PDE4 inhibitory properties. In the International Patent Application WO94/12461 and in the European Patent Application EP 0 763 534 3-aryl-pyridazin-6-one and arylalkyl-diazinone derivatives are described as selective PDE4 inhibitors.
It has now been found that the morpholino-derivatives, which are described in greater details below, have surprising and particularly advantageous properties.
The invention thus relates to compounds of formula I 
in which
R1 and R2 are both hydrogen or together form an additional bond.
Ar represents a benzene derivative of formula (a) or (b) 
wherein
R3 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is halogen, 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R5 is halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is 1-4C-alkyl and
R7 is hydrogen or 1-4C-alkyl,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom,
B represents C(O) (carbonyl) or S(O)2 (sulfonyl),
A represents O (oxygen), S (sulfur), S(O) (sulfinyl) or S(O)2 (sulfonyl),
and the salts of these compounds.
1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
1-8C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Alkoxy radicals having 1 to 8 carbon atoms which may be mentioned in this context are, for example, the octyloxy, heptyloxy, isoheptyloxy (5methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
Halogen within the meaning of the present invention is bromine, chlorine and fluorine.
3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopenlyloxy are preferred.
3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.
1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy and in particular the 1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred. xe2x80x9cPredominantlyxe2x80x9d in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms.
As spiro-linked 5-, 6- or 7-membered hydrocarbon rings, optionally interrupted by an oxygen or sulphur atom, may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydropyran and the tetrahydrothiophen ring.
Suitable salts for compounds of the formula I are all acid addition salts. Particular mention may be made of the pharmacologically tolerable inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparationxe2x80x94depending on whether a mono- or polybasic acid is concerned and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts, which can be obtained, for example, as process products during the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
According to expert""s knowledge the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of formula I as well as all solvates and in particular all hydrates of the salts of the compounds of formula I.
Compounds of formula I to be emphasized are those in which
R1 and R2 are both hydrogen or together form an additional bond,
Ar represents a benzene derivative of formula (a) or (b) 
wherein
R3 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R5 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is 1-4C-alkyl and
R7 is hydrogen or 1-4C-alkyl,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,
B represents C(O) (carbonyl) or S(O)2 (sulfonyl),
A represents O (oxygen), S (sulfur), S(O) (sulfinyl) or S(O)2 (sulfonyl),
and the salts of these compounds.
Compounds of formula I which are particularly to be emphasized are those in which
R1 and R2 together form an additional bond,
Ar represents a benzene derivative of formula (a) or (b) 
wherein
R3 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is 1-4C-alkoxy,
R5 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is methyl,
R7 is hydrogen,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane or cyclohexane ring,
B represents C(O) (carbonyl) or S(O)2 (sulfonyl),
A represents O (oxygen), S (sulfur), S(O) (sulfinyl) or S(O)2 (sulfonyl),
and the salts of these compounds.
Preferred compounds of formula I are those in which
R1 and R2 together form an additional bond,
Ar represents a benzene derivative of formula (a) or (b) 
wherein
R3 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is 1-4C-alkoxy,
R5 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is methyl,
R7 is hydrogen,
B represents C(O) (carbonyl) or S(O)2 (sulfonyl),
A represents O (oxygen), S (sulfur), S(O) (sulfinyl) or S(O)2 (sulfonyl),
and the salts of these compounds.
Especially preferred compounds of formula I are those in which
R1 and R2 together form an additional bond,
Ar represents a benzene derivative of formula (a) or (b) 
wherein
R3 is ethoxy,
R4 is ethoxy,
R5 is methoxy,
R6 is methyl,
R7 is hydrogen,
B represents C(O) (carbonyl) or S(O)2 (sulfonyl),
A represents O (oxygen), S (sulfur) or S(O)2 (sulfonyl),
and the salts of these compounds.
One embodiment (embodiment a) of the compounds of formula I are those in which
R1 and R2 are both hydrogen or together form an additional bond,
Ar represents a benzene derivative of formula (a) or (b) 
wherein
R3 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is halogen, 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R5 is halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is 1-4C-alkyl and
R7 is hydrogen or 1-4C-alkyl,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom,
B represents C(O) (carbonyl),
A represents O (oxygen) or S (sulfur),
and the salts of these compounds.
Compounds of formula I of embodiment a to be emphasized are those in which
R1 and R2 are both hydrogen or together form an additional bond.
Ar represents a benzene derivative of formula (a) or (b) 
wherein
R3 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R5 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is 1-4C-alkyl and
R7 is hydrogen or 1-4C-alkyl,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,
B represents C(O) (carbonyl),
A represents O (oxygen) or S (sulfur),
and the salts of these compounds.
Compounds of formula I of embodiment a which are particularly to be emphasized are those in which
R1 and R2 together form an additional bond,
Ar represents a benzene derivative of formula (a) or (b) 
wherein
R3 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is 1-4C-alkoxy,
R5 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R6 is methyl,
R7 is hydrogen,
or wherein
R6 and R7 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked cyclopentane or cyclohexane ring.
B represents C(O) (carbonyl),
A represents O (oxygen) or S (sulfur),
and the salts of these compounds.
Preferred compounds of formula I of embodiment a are those in which
R1 and R2 together form an additional bond,
Ar represents a benzene derivative of formula (a) or (b) 
wherein
R3 is methoxy or ethoxy,
R4 is ethoxy,
R5 is methoxy,
R6 is methyl,
R7 is hydrogen,
B represents C(O) (carbonyl) and
A represents O (oxygen) or S (sulfur),
and the salts of these compounds.
The compounds of formula I are chiral compounds. Chiral centers exist in the compounds of formula I in the positions 4a and 8a. In case Ar represents a benzene derivative of formula (b) there is one further chiral center in the dihydrofuran-ring, if the substituents xe2x80x94R6 and xe2x80x94CH2R7 are not identical. However, preferred are in this connection those compounds, in which the substituents xe2x80x94R6 and xe2x80x94CH2R7 are identical or together and with inclusion of the two carbon atoms to which they are bonded form a spiro-connected 5-, 6- or 7-membered hydrocarbon ring. 
Therefore the invention includes all conceivable pure diastereomers and pure enantiomers, as well as all mixtures thereof independent from the ratio, including the racemates. Preferred are those compounds, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated. Especially preferred in this connection are those compounds, in which the absolute configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position 4a and R in the position 8a. Racemates can be split up into the corresponding enantiomers by methods known by a person skilled in the art. Preferably the racemic mixtures are separated into two diastereomers during the preparation with the help of an optical active separation agent on the stage of the cyclohexanecarboxylic acids or the 1,2,3,6-tetrahydrobenzoic acids (for example, starting compounds A3 and A4). As separation agents may be mentioned, for example, optical active amines such as the (+)- and (xe2x88x92)-forms of 1-phenylethylamine [(R)-(+)-1-phenylethylamine=(R)-(+)-xcex1-methylbenzylamine or (S)-(xe2x88x92)-1-phanylethylamine=(S)-(xe2x88x92)-xcex1-methylbenzylamine) and ephedrine, the optical active alkaloids quinine, cinchonine, cinchonidine and brucine.
The compound according to the invention can, for example, be prepared as described in Reaction Scheme 1. In a first step the cyclohexanecarboxylic or 1,2,3,6-tetrahydrobenzoic acids are reacted with 4-hydrazinobenzoic acid or 4-hydrazinobenzene sulfonic acid. The resulting compounds are activated, for example, with phosphorus pentachloride or oxalyl chloride and then treated with morpholine or thiomorpholine.
Oxidised thiomorpholine derivatives of formula I can be prepared for example starting from the corresponding thiomorpholine derivatives of formula I using standard oxidation methods, preferably m-chloroperbenzoic acid in dichloromethane at 0xc2x0 C. 
Suitably, the conversions are carried out analogous to methods which are familiar per so to the person skilled in the art, for example, in the manner which is described in the following examples.
The preparation of the cyclohexanecarboxylic acids and 1,3,5,6-tetrahydrobenzoic acids is described, for example, in WO98/31674 and WO99/31090.
The substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent (for example a ketone like acetone, methylethylketone, or methylisobutylketone, an ether, like diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol, such as ethanol, isopropanol) which contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification into the free compounds which, in turn, can be converted into salts. In this manner, pharmacologically non-tolerable salts can be converted into pharmacologically tolerable salts.
The following examples illustrate the invention in greater detail, without restricting it. As well, further compounds of formula I, of which the preparation is explicitly not described, can be prepared in an analogous way or in a way which is known by a person skilled in the art using customary preparation methods.
The compounds, which are mentioned in the examples as well as their salts are preferred compounds of the invention.